Lessons Learned from Clinical Development to

Licensure of Vaccines

Myron M. (Mike) Levine, M.D., D.T.P.H.Associate Dean for Global Health, Vaccinology and

Infectious Diseases,

Center for Vaccine Development,

University of Maryland School of Medicine

Baltimore, MD

Mahidol University, Bangkok, Thailand, Aug 5, 2016

Disease

Burden

Public

perception

Scientific

feasibility

Basic

vaccine

research

Process

developmentLarge-scale

manufacture

Vaccine

candidates

LICENSED

PRODUCT

Phase

1

Phase

2

Phase

3

Pilot lots

P

o

s

t-

l

i

c

e

n

s

u

r

e

Pre-clinical

NRA

Time & costs:

8-15 years

$60-900 million

THE VACCINE

DEVELOPMENT PARADIGM

Phase

4

Refinement of

process & scale-up

Vaccine development:

the really big costs

• Huge financial risk – Few vaccines that enter Phase 1 trials ever reach Phase 3

• The further a vaccine candidate progresses along the development paradigm, the lower the risk

• Clinical trials

–Phase 1

–Phase 2

–Phase 3

• Construction and

furbishment of the

manufacturing

establishment

DISEASE BURDEN, MARKETS & VACCINE DEVELOPMENT

“Global market vaccines” - e.g., Hepatitis B, Hib, rotavirus, pneumo

• Burden in both industrialized and developing countries

• Markets in industrialized countries drive development

“Industrialized market vaccines” - e.g., Lyme disease; nicotine

• Burden & markets in industrialized countries drive development

“Impeded vaccines” - e.g., RSV, group A Streptococcus pyogenes

• Markets exist but safety questions raise the risk and create barriers

“Developing market vaccines” - e.g., malaria, Shigella, Leishmania

• Burden in developing countries; few “reliable” or “mature” markets

“Biodefense vaccines” - e.g., anthrax, tularemia, Ebola, smallpox

• Burden is theoretical; governments create the market

“Pandemic vaccines” - e.g., Swine flu 1976 & 2009, Avian flu 2006

• Burden sometimes unclear; gov’ts must guarantee a market

Emerging pathogen vaccines - e.g., Ebola 2014-2015, Zika 2016

GAVI & gov’ts must guarantee a market; industry sees some market

The Center for Vaccine

Development (CVD) of the

University of Maryland

School of Medicine, an Academic

Vaccine Development Enterprise

Brief history, mission, organizational

structure and some global health

highlights

1974 -- The year that CVD was born

• National Commission for the Protection of

Human Subjects in Biomedical and

Behavioral Research (1974; birth of IRBs)

• Recombinant DNA technology did not exist

(Asilomar conference was 1975)

• Vaccinology was not a discipline

• CVD had only 9 staff!

Evolution of the CVD, 1974 - 2014

• 1974-76 -- Clinical Research Center for Vaccine

Development (CRCVD) (NIH-supported clinical trials)

---------------------------------------------------------------------------------

• 1976 -- Center for Vaccine Development (CVD)

Research scope expanded to include:

• Basic vaccine development (vaccine candidate construction)

• Disease burden studies in developing countries

• Large-scale field trials of efficacy in developing countries

1984 - Division of Geographic Medicine, Dep’t of

Medicine

1984 - Division of Infectious Diseases & Tropical

Pediatrics, Dep’t of Pediatrics

Orientation and Missions of the CVD

Orientation: Vaccinology & Global Health

Missons:

Research

Education

Clinical care

Service (University, community,

national, international)

Vaccines of interest to CVDVaccines against diseases that mainly afflict populations in the developing world and for which there do not exist substantial markets in industrialized countries (other than travelers). Historically, development of these vaccines was not a high priority of the industrialized country vaccine manufacturers (“big pharma”).

Pre-September 11, 2001: Enteric diseases (cholera, typhoid & paratyphoid fever, Shigella, ETEC), malaria, mucosal vaccines, combination vaccines, single-dose vaccines, vaccines for early infancy & the elderly, pneumococcus, Hib, Group A S. pyogenes

Post-September 11, 2001 (for one decade): Biodefense vaccines were a major interest.

Post-2005: Vaccines against emerging infections became another focus (invasive NTS 2005 ; Ebola 2014)

A self-contained academic vaccine development enterprise

Basic research Animal models

Pediatric Phase

1 & 2 trials, USA

Adult Phase 1 & 2

clinical trials, USA

Pediatric Phase

1 & 2 trials, abroad

Adult Phase 1 & 2

trials, abroad

Phase 3 field

trials, USA

Phase 3 field

trials, abroadPublic policy

Epidemiologic research

Regulatory affairs

Microbiology &

molecular

diagnostics

Biostatistics

Immune response

measurement

Domestic clinical

research

Off-shore clinical

research

CLINICAL RESEARCH CAPABILITIES

CVD does not manufacture GMP pilot

lots of its own vaccine candidates for

early clinical trials.

However, CVD does prepare non-GMP

pilot formulations of its enteric bacterial

vaccines for oral immunization

CVD off-shore units as of 2014

CVD-Baltimore (130 staff, including 30

faculty)

CVD-Chile (12 staff) (~ 75 in 1990s)

Roberto del Rio Children’s Hospital,

Area Norte, Santiago, Chile

CVD-Mali

Bandiagara Malaria Project (50 staff)

CVD-Mali, Bamako (> 400 staff)

CVD-Malawi (35 staff)

CVD-CHILE

CVD-MALI

CVD-Mali -- Undertaking public health interventions and

vaccinology field research and laboratory projects in one of

the world’s least developed countries

CVD-Mali Phase 1 trial with ChAd3-EBO-Z, Oct. 8, 2014

-80o C

freezer

Some vaccines in the CVD pipeline

CVD 103-HgR - Single-dose live oral cholera vaccine licensed by the FDA (2016) to prevent cholera in US travelers (manufactured by PaxVax).

CVD 909 - Live typhoid vaccine expressing Vi antigen constitutively (Phase 2) (Licensed by Bharat)

CVD 1902 S. Paratyphi A (Phase 1) (Bharat)

CVD 908-htrA -- Single-dose live oral typhoid vaccine used as a live vector. Well-tolerated & immunogenic in Phase 2 trials.

Quadrivalent Shigella vaccine (prototype, S. flexneri 2a CVD 1208S. (Phase 2).

Combination live vector Shigella-ETEC oral vaccine (Phase 2).

NTS bivalent conjugate – Pre-clinical (Bharat)

NTS live oral vaccine – Pre-clinical

pMSINH -- New measles DNA vaccine for very young infants in developing countriesAnthrax, plague & tularemia vaccines

CVD has been a global leader in

disease burden measurement

• State-of-the-art diagnostic methods

combined with impeccable epidemiologic

designs

• Building of regional and global consortia

• South-South, as well as North-South

collaborations

• Innovation in seroepidemiology

Disease burden, etiology & diversity

• Global Enteric Multicenter Study

(GEMS) – case/control design

– 4 sites in sub-Saharan Africa, 3

sites in South Asia linked to DSS

– Tested for > 40 diarrheal pathogens

– 4 pathogens paramount (~ 50% of

all moderate-to-severe diarrhea)

– Considerable post-acute mortality

– Shigella serotypes & ETEC CFAs

• Invasive bacterial infections, Mali

– Importance of non-typhoidal

Salmonella in West Africa

Field trials of Ty21a live oral typhoid

vaccine in Santiago, Chile that led to FDA

licensure

The trials:

• 4 large-scale, randomized controlled field trials

• ~ 463,937 schoolchildren 5-19 years of age

• Followed 3-7 years

The partners:

• Ministry of Health, Chile

• Center for Vaccine Development, U. Maryland

• WHO

• U.S. Department of Defense

• Pan American Health Organization

Levine et al 1987; 1990; 1999; 2007;

Ferreccio et al 1989; Black et al 1990;

CVD training legacy

Education product:

• CVD alumni in important positions in:– Academia

– Government (NIH, CDC, FDA, Department of Defense)

– Foundations, NPO

• T32 Vaccinology Training Grant

• CVD alumni in important positions in other

countries

The key to CVD

accomplishments

The spectacular and dedicated CVD faculty,

staff and trainees

Assessing vaccine efficacy pre-licensure

• “Gold Standard” -- Large-scale, adequately-powered, randomized, controlled, double-blind trial with allocation at the level of the individual

• Trials with cluster randomization of larger units such as classes, schools, families, villages

• Seroprotection (immunologic correlate of protection known) or serological non-inferiority

• Mass interventions; “before and after” analysis

• Volunteer challenge studies

• FDA “Animal model rule” (e.g., biodefense vaccines, intermittent unpredictable burden, etc.)

• Accelerated approval

Lessons Learned from Clinical

Development to Licensure of a

Single-Dose Live Oral Cholera

Vaccine, Strain CVD 103-HgR

Cholera

• A potentially very severe diarrheal disease (cholera gravis) that leads to dehydration, hypovolemic shock, renal failure and death if appropriate rehydration therapy is not promptly instituted

• Rice water stools of cholera contain body water and concentrations of electrolytes resembling serum levels

Vibrio cholerae

• > 200 V. cholerae O serogroups

• Two serogroups cause epidemic cholera:

– O1 > 99% of all cases globally

• Biotypes

El Tor & Classical

Hybrid – El Tor expressing Classical cholera toxin

• Serotypes

– Inaba

– Ogawa

– Hikojima (very rare)

– O139 (rare)

Pathogenesis of cholera

• Passage through the gastric

acid barrier to reach the

proximal small intestine

• Directed motility of vibrios

(involves chemotaxis)

• Attachment to enterocytes by

means of Toxin Co-Regulated

Pili (TCP)

• Export of cholera enterotoxin

(ctx)

• Tight regulation of expression of

TCP and CTX by toxR

SJ Krebs

&

RK Taylor

2011

Epidemiologic behavior of cholera

Rwandan refugees,

Goma, Zaire, 1994

Bangladeshi

refugees,

India, 1971

• Environmental reservoir (brackish water)

• Transmitted by contaminated water &

food

• Exhibits true pandemic behavior (El Tor

is the 7th pandemic)

• Causes explosive epidemics

• Highly seasonal in endemic areas

• “Virgin soil epidemics” – Enormous

disease burdens and high case when

cholera first invades previously unaffected,

immunologically-naïve, populations where

the health infrastructure is unfamiliar with

the treatment of cholera

Chicago Tribune, June 3, 1958

Cholera epidemic in Bangkok,

Cholera Kills 106 Over Week-End in Thailand BANGKOK, Thailand, June 2 (A - The death toll in I Thailand's cholera epidemic climbed to 106 over the week- end. The disease has infected 719 in the last 10 days. The health department reported a slight decline in the number of cases reported and there were no reports of infection among the large foreign community.

Robert A. Phillips, Capt., MC,

USN

From the US Naval Medical

Research Unit, Taipei, Taiwan

In 1958 and 1959 the U.S. Naval

Medical Research Unit No.2

(NAMRU-2), at the invitation of

the Thai Government, conducted

studies at Chulalongkorn

Hospital in Bangkok on patients

suffering from cholera. In 1959 a

joint NIH/WRAIR/NAMRU team

went to Bangkok.

Cholera epidemic

in Bangkok,

1958 & 1959

Phillips at NAMRU-3 in Cairo,

1948

Biopsy of Thai cholera patient using a Crosby

biopsy capsule, late 1950s. Gangarosa EJ et al. Am J Trop Med Hyg 1960

Eugene J Gangarosa, MD

Bangkok, Thailand, 1959

The US/Thai team subsequently performed biopsies

of healthy Thai adults. They exhibited the same

mucosal morphology as the cholera patients. So

cholera wasn’t responsible for the observed

intestinal morphology.Sprinz H, Sribhibhad R, Gangarosa EJ, Benyajati C, Kundel D,

Halstead SB. Am J Clin Path 1962; 38:43-51

Scott B Halstead

Potential uses and target

populations for cholera vaccines

• To control epidemic cholera

• Mass immunization of high-risk target populations (e.g., refugees)

• To control seasonal increases of cholera in endemic areas

• Protect travelers to areas where cholera is endemic or epidemic

Licensed cholera vaccines, old and new

Old parenteral vaccines Dosing regimen

• Inactivated V. cholerae O1 1-2 doses

Modern oral vaccines

• Inactivated whole V. cholerae O1 2 doses,

plus B subunit (Dukoral®) 2 weeks apart

• Inactivated whole V. cholerae O1 2 doses,

& O139 without B subunit 2 weeks apart

(Shanchol™ & Euvichol®)

• Engineered attenuated V. cholerae O1 Single-dose

strain CVD 103-HgR (Vaxchora®)

(previously Orochol®, Mutacol®, & Orochol E®)

CVD volunteer model of experimental cholera

• Established in 1976 at the behest of the US Cholera Panel of NIH

to test a toxoid vaccine.

• Healthy adult community volunteers.

• Performed on CVD Research Isolation Ward under QUARANTINE.

• High attack rate of diarrhea.

• Objective outcomes measured (diarrheal volume, vomiting, fever).

• Precise quantitation of diarrheal stool volumes.

• A proportion of subjects develop copious purging (0.5 - 1.1 liters per

hour). (> 5 liter purge = “severe” cholera; > 3 liter purge = “moderate”

cholera).

• Aggressive oral & IV rehydration & early antibiotic therapy.

• Prior cholera & some vaccines are highly protective in this model.

• This model has proved invaluable for studying pathogenesis of and

immunity to cholera, relevant to vaccine development.

A cholera challenge study is underway at the CVD

Research Isolation Ward

Original CVD Research Isolation Ward (1970s)

Levine MM et al, Trans Roy Soc Trop Med Hyg 1979

Experimental cholera challenge of US volunteers

immunized with 3 monthly 8 mg enteral doses of

purified glutaraldehyde-treated cholera toxoid

JOURNAL OF INFECTIOUS DISEASES

1971; 123:61-65

“The duration of immunity derived from cholera infection is short, especially in persons whose subsequent reinfection is due to heterologous organisms. The risk of reinfection with V. cholerae is probably only slightly less than the risk of initial infection. The relatively high frequency of reinfection indicates that an effective cholera vaccine will need to stimulate greater immunity than does the natural disease.”

Dogma on disease-derived immunity

to cholera, circa 1970

Relationship between

serum reciprocal

vibriocidal antibody

titer and cholera case

rate per 103, Matlab

Bazar

(Mosley WH et al, Bull WHO

1968; 38:327-334)

Bull WHO 1968; 38:777-785

Baseline

vibriocidal titer

Total no. of

family contacts

No. of contacts with culture-

confirmed cholera diarrhea

<20 190 28 (14.7%)

20 65 4 (6.2%)

40 65 4 (6.2%)

80 42 1 (2.4%)

> 160 59 1 (1.7%)

Protective immunity conferred by clinical classical

Ogawa cholera upon subsequent homologous

challenge of US volunteers with V. cholerae O1

classical biotype serotype Ogawa

Levine MM et al, Trans Roy Soc Trop Med Hyg 1979

Immunity following clinical cholera

in U.S. volunteers

Positive

Attack Rate Coprocultures

Biotype Ctrls Vets Efficacy Ctrls Vets

Classical 24/27 0/16 100% 26/27 0/16

p = 0.012

El Tor 32/37 2/22 90% 34/37 8/22

* Levine et al, 1978, 1981, 1983

Serum vibriocidal antibody (Clements ML et al, J Infect Dis)

Long-term immunity in North Americans

elicited by prior clinical cholera

Attack Rate*

Controls 4/5p=0.04

Re-challenge veterans** 0/4p<0.001

Cumulative controls 26/28

* Attack rate following challenge with 106 classical Ogawa 395. ** These four subjects experienced classical biotype cholera 33-36 months earlier following experimental challenge (3 had Ogawa and 1 Inaba). (Data from Levine et al, J Infect Dis 1981)

Immunologic responses of cholera “veterans” & controls

to challenge with 106 V. cholerae O1 classical Ogawa

Serum Serum Intestinal

Diarrhea Excret. V’dal Titer IgG anti-CT SIgA anti-CT

Subj. Volume of V. ch. Pre Peak Pre Peak Pre Peak

Veterans (Levine et al, J Infect Dis 1981)

-5 0 0 80 80 0.36 0.39 <8 <8

-14 0 0 20 20 1.06 1.00 <8 <8

-10 0 0 80 320 0.18 0.89 <8 32

-9 0 104 160 5120 0.68 1.18 <8 >64

Controls

-1 7.1 liters 107 <20 1280 0.06 1.35 <8 <8

-7 2.1 ” 108 <20 1280 0.07 0.51 <8 <8

-8 7.2 ” 107 <20 320 0.09 1.23 <8 <8

-13 5.3 ” 106 20 10240 0.12 1.13 <8 <8

-6 0 105 160 5120 0.40 1.34 <8 16

Natural infection-derived immunity in

Bangladesh following clinical cholera caused

by different biotypes:

field studies corroborated volunteer data

Initial Subsequent Protective

Study Infection Infection Efficacy

Glass Mostly Mostly 90%

1982 Classical Classical

Clemens Classical Classical 100%

1991 Classical El Tor 100%

El Tor El Tor 29%

El Tor Classical 0%

Response of healthy adult volunteers after ingesting various doses of cholera

toxin

Cholera enterotoxin alone can cause cholera gravisMM Levine et al. Enteric infections and vaccine development. Micro Rev 1983

Volunteer Cholera toxin Incubation Total diarrheal No diarrheal Durationdose (mcg) (hours) purge (ml) stools (hours)

Insights on mechanisms of

immunity against cholera:

anti-bacterial immunity is key

89% vaccine efficacy of V. cholerae O1 El Tor Inaba vaccine

strain JBK 70 (ctx deletion) in protecting against challenge

with virulent El Tor Inaba N16961

Group Diarrhea

Attackrate

Mean

diarrheal

stool

volume per

ill volunteer (range)

No. with

positive

direct

stool cultures

Geometric

mean

excretion

(vibrios per g stool)

Controls7/8

4.5 liters

(1.1-7.9 l)8 4x106

P<0.003 P<0.001

Vaccinees 1/10 1.6 liters 2 4x103

Challenge with 106 cfu of virulent El Tor Inaba N16961 one month after ingestion of

a single oral dose of vaccine Levine et al. Infect Immun 1988

Cholera challenges in

volunteers to assess efficacy

of candidate vaccines in

preventing cholera

Serum vibriocidal antibody correlates with

protection against cholera

• Serum vibriocidal antibody may be a proxy for a protective

intestinal immune response.

• Most vibriocidal antibody is anti-LPS, some is directed

against (poorly characterized) protein antigens

• In general, the stronger the vibriocidal response, the greater

the protective effect.

• In US volunteers, vibriocidal antibody titers drop rapidly

towards (but do not reach) baseline after clinical cholera (or

oral vaccine) but protection endures long thereafter.

• Vibriocidal antibody response is particularly useful for

assessing the relative immunogenicity of oral vaccines

in non-immune hosts.

CVD 103-HgR live

oral cholera

vaccine• Vibrio cholerae O1

• Classical biotype, Inaba

serotype

• ctxA deleted, ctxB intact

• Hg++ resistance gene

inserted into hlyA locus

• Makes toxin co-

regulated pili (TCP)

Immunogenicity of CVD 103-HgR

(Orachol/Mutacol) in US adult subjects*

Levine & Kaper Kotloff

1993 1992

No. subjects 182 94

> 4-fold v-dal rise 93% 97%

V’dal titers > 2560 50% 67%

Reciprocal GMT (Inaba) 1699 2656

IgG antitoxin rises 81% 72%

* A single 5x108 CFU dose

Efficacy of single-dose Orochol®/Mutacol®

CVD 103-HgR in preventing cholera

Severity Vacc Ctrls Efficacy p

> 5.0 liters 1/103 10/86 92% <.0029

> 3.0 liters 1/103 16/86 95% <.0001

----------------------------------------------------------------------------------------------------------------------------- -----------

> 1.0 liter 8/103 41/86 84% <.0001

Any 19/103 73/86 78% <.001

Composite of 8 separate challenges with El Tor Inaba, El Tor Ogawa, classical Inaba and classical Ogawa

Significant protection is already present 8 days after ingesting the single dose

Efficacy of CVD 103-HgR (Mutacol®) in

preventing moderate and severe El Tor

cholera when challenged > 3 months

after ingestion of a single oral dose

Cholera

Attack Rate Vacc Ctrls Efficacy

Moderate/severe 1/28 9/23 91%

(i.e., > 3.0 liters) 3.6% 39.1% (51-99%)*

Challenge with 105 CFU of NIH El Tor Inaba N16961 frozen inoculum

Data from Tacket, Cohen et al, Infect Immun 1999 * (95% CI)

This study design was requested by the FDA

PaxVax Vaxchora™ (CVD 103-HgR) protects against

experimental challenge with V. cholerae O1

Parameter measured

after challenge

Vaccine

10-Day

post

N=35

Vaccine

3-Month

post

N=33

Placebo

N=66

Attack Rate ≥ 3 Liter

liquid stool2/35 (6%) 4/33 (12%) 39/66 (59%)

Vaccine Efficacy 90% 80%

Lower Bound of 95% CI 63% 50%

Challenge with 105 CFU of NIH El Tor Inaba N16961 frozen inoculum This study was designed in conjunction with the FDA

Chen WH et al, Clin Infect Dis 2016

Figure 1. Correlation of serum vibriocidal antibody titer fold-increase in response to vaccination and cumulative diarrheal purge volume following

cholera challenge

1 416

64

256

1024

4096

0

5

1 0

1 5

2 0

2 5

F o ld - in c re a s e in s e ru m v ib r io c id a l a n tib o d y re c ip ro c a l t ite r

fo llo w in g in g e s tio n o f C V D 1 0 3 -H g R o r p la c e b o

1 0 -d a y V a c c in e e , n = 3 5

1 0 -d a y P la c e b o , n = 3 3

 

Cu

mu

lati

ve

Dia

rrh

ea

(L

)

1 416

64

256

1024

4096

0

5

1 0

1 5

2 0

2 5

F o ld - in c re a s e in s e ru m v ib r io c id a l a n tib o d y re c ip ro c a l t ite r

fo llo w in g in g e s tio n o f C V D 1 0 3 -H g R o r p la c e b o

  

Cu

mu

lati

ve

Dia

rrh

ea

(L

)

3 -m o n th V a c c in e , n = 3 3

3 -m o n th P la c e b o , n = 3 3

r = -0.75

p<0.0001

r = -0.69

p<0.0001

Chen WH et al. Clin Infect Dis 2016

4 of 6 vaccinees who did not seroconvert (67%) got moderate-to-severe cholera versus 2 of 62 who seroconverted (3.2%), p=0.00026

1

2

3

4

Lo

g 1

0 T

iter S

VA

GM

T

Visit Day

Time Course Plot of vibriocidal GMT against

Classical Inaba V. cholerae O1

Challenge

Lot

Older

Total Placebo

80% efficacy after day 91

90% efficacy after day 11 challenge

Vaxchora: Efficacy Demonstrated in HumanChallenge Correlates with Immune Response

PaxVax Presentation - ACIP 24 Feb 2016 57

Forest Plot of Vibriocidal Antibody Seroconversion (95% CI) against Classical Inaba V. cholerae Through Day 11 Immunogenicity Evaluable Population

Note: N analyzable: Phase 1=54; Challenge=93; Lot=2687; Older=291; Combined placebo=544.Source: Figure 11.4.1; Table 11.3.1.1; Phase 1 (CSR PXVX-VC-200-002); challenge (CSR PXVX-VC-200-003); lot consistency (CSR PXVX-VC-200-004); older adult (CSR PXVX-VC-200-005).

PXVX0200 (Vaxchora) is immunogenic~90% seroconversion in Phase 3 studies

PaxVax Presentation - ACIP 24 Feb 2016 58

Phase 1

Challenge

Lot consistency

Older adult

Combined placebo

Seroconversion Rate (%)

Situations where single-dose live oral cholera vaccine CVD 103-HgR fills a

void in cholera control

• The single-dose live oral vaccine shows strong

efficacy as early as 8-10 days after immunization

• Useful for travelers

• Also potentially as an adjunct tool to help control

explosive “virgin soil” outbreaks of cholera

• Use of CVD 103-HgR in developing country

populations requires a 1-log higher dosage level of

vaccine organisms (109 CFU) than is used in

industrialized country travelers

Infection & Immunity 1989; 57:3261-3264

K Ladawan, Drs. Wichai Supanaranond, Benjaluk

Prayurahong, , Sricharoen Migasena, Pravan Suntharasamai,

Mike Levine and Danai, VTC ~ 1988

SERUM VIBRIOCIDAL ANTIBODY

RESPONSE OF 5-9 YEAR OLD INDONESIAN

CHILDREN TO SINGLE-DOSE CVD 103-HgR

LIVE ORAL CHOLERA VACCINE

Dose Seroconversion Peak GMT

Placebo 2/56 (4%) 50

5x106 3/58 (5%) 45

5x107 3/62 (5%) 61

5x108 12/77 (16%) 88

------------------------------------------------------------------

5x109 21/28 (75%) 453

1x1010 26/32 (81%) 433

Data from Suharyono et al, Lancet 1992

CVD

Environmental enteropathy U.S. infant

• In children & adults living in underprivileged, fecally-contaminated conditions

• Small bowel bacterial overgrowth

• Striking histopathological changes in the small intestine (U Fagundes Neto 1997)

---------------------------------------------------------------------

• Small bowel bacterial overgrowth diminishes the vibriocidal response to CVD 103-HgR in children in developing countries

• 202 fasting Santiago schoolchildren age 5-9 yrs

• Lactulose breath H2 tests to detect proximal small

bowel bacteria, one day before ingesting 109 CFU

of CVD 103-HgR.

• Small bowel overgrowth associated with diminished

seroconversion (p=0.04) (Lagos et al 1999)

Environmental

enteropathy in

a Brazilian

toddler

ASSESSMENT OF LIVE ORAL VACCINE EFFECTIVENESS, MICRONESIA OUTBREAK• 47% of population vaccinated during mass

campaign

• Retrospective cohort study of target population vaccinated

• Match between cholera case records

& vaccination registries

• Cholera incidence 5x higher in non-vaccinees

• Estimated Vaccine Efficacy = 79% (CI, 72-85%)

Vaccine efficacy evaluation team led by Dr. Claire-Lise Chaignat,

Global Task Force on Cholera Control, WHO

Calain P et al, Vaccine 2004; 22:2444-2451

Thank you